CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.

Corella, Dolores; Asensio, Eva María; Coltell, Oscar; Sorlí, José Vicente; Ramón, Estruch; Martínez-González, Miguel Ángel, 1957-; Salas-Salvadó, Jordi; Castañer, Olga; Arós, Fernando; Lapetra, José; Serra-Majem, Luis; Gómez-Gracia, Enrique; Ortega‑Azorín, Carolina; Fiol, Miquel; Díez Espino, Javier; Díaz‑López, Andrés; Fitó Colomer, Montserrat; Ros, Emilio; Ordovás, José M.

CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.

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dc.contributor.author Corella, Doloresca
dc.contributor.author Asensio, Eva Maríaca
dc.contributor.author Coltell, Oscarca
dc.contributor.author Sorlí, José Vicenteca
dc.contributor.author Ramón, Estruchca
dc.contributor.author Martínez-González, Miguel Ángel, 1957-ca
dc.contributor.author Salas-Salvadó, Jordica
dc.contributor.author Castañer, Olgaca
dc.contributor.author Arós, Fernandoca
dc.contributor.author Lapetra, Joséca
dc.contributor.author Serra-Majem, Luisca
dc.contributor.author Gómez-Gracia, Enriqueca
dc.contributor.author Ortega‑Azorín, Carolinaca
dc.contributor.author Fiol, Miquelca
dc.contributor.author Díez Espino, Javierca
dc.contributor.author Díaz‑López, Andrésca
dc.contributor.author Fitó Colomer, Montserratca
dc.contributor.author Ros, Emilioca
dc.contributor.author Ordovás, José M.ca
dc.date.accessioned 2016-04-18T09:55:28Z
dc.date.available 2016-04-18T09:55:28Z
dc.date.issued 2016
dc.description.abstract BACKGROUND: Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. METHODS: We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. RESULTS: We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43-0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63-1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model. CONCLUSIONS: In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.ca
dc.description.sponsorship This study was funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad (Projects PI051839, PI070240, PI1001407, G03/140, CIBER 06/03, RD06/0045 PI07-0954, CNIC-06, PI11/02505, SAF2009-12304, AGL2010-22319-C03-03 and PRX14/00527), Fondo Europeo de Desarrollo Regional, by the University Jaume I (Project P1-1B2013-54) and by the Generalitat Valenciana (AP111/10, AP-042/11, BEST/2015/087, GVACOMP2011-151, ACOMP/2011/145, ACOMP/2012/190 and ACOMP/2013/159). This material is based upon work supported by the U.S. Department of Agriculture—Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003
dc.format.mimetype application/pdfca
dc.identifier.citation Corella D, Asensio EM, Coltell O, Sorlí J, Estruch R, Martínez-González MÁ et al. CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial. Cardiovasc Diabetol. 2016 Jan 7;15(1):4. doi: 10.1186/s12933-015-0327-8.ca
dc.identifier.doi http://dx.doi.org/10.1186/s12933-015-0327-8
dc.identifier.issn 1475-2840
dc.identifier.uri http://hdl.handle.net/10230/26104
dc.language.iso engca
dc.publisher Springer Verlagca
dc.relation.ispartof Cardiovascular Diabetology. 2016 Jan 7;15(1):4
dc.rights © 2016 Corella et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
dc.subject.other Diabetisca
dc.subject.other Sistema cardiovascular -- Malalties -- Aspectes genèticsca
dc.subject.other Dieta -- Mediterrània, Regió de laca
dc.title CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.ca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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